Molecular Response at 3 Months On Nilotinib Therapy Predicts Response and Long-Term Outcomes in Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Abstract Abstract 3292 Poster Board III-1 Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of Philadelphia positive CML patients (pts) in CP or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. A recent analysis demonstrated an association between BCR-ABL transcript levels at 3 months (mos) and response in pts treated with second-line tyrosine kinase inhibitors (Branford et al. Blood. 2008). This multi-center analysis was conducted to examine the association specifically between the initial molecular response to nilotinib with response and outcomes. Methods: CML-CP pts (N = 321) with imatinib resistance or intolerance were included and post-baseline BCR-ABL transcript levels were available for 294 patients. Intolerant pts also exhibited some degree of resistance to imatinib and were not eligible for the study if demonstrating major cytogenetic response (MCyR), the primary study endpoint. We aimed to determine if the initial molecular response to nilotinib could predict the response and outcome of patients with or without BCR-ABL mutations at baseline or those with imatinib resistance or intolerance. BCR-ABL transcript levels at 3 mos were used to perform a landmark analysis to assess the association between the initial molecular response and estimated probability of MCyR, major molecular response (MMR), and event-free survival (EFS) at 24 mos. Events were defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to progression or death. The analysis excludes patients who had already attained MCyR (n = 111) or MMR [BCR-ABL% (IS) ≤ 0.1%] (n = 28) or who had an event (n = 22) within the first 3 mos of therapy for each respective landmark analysis. Patients censored within the first 3 mos were also excluded. Patients were then grouped according to their level of BCR-ABL% (IS). Results: BCR-ABL% (IS) at 3 mos correlated with MCyR rates at 24 mos; pts with BCR-ABL% (IS) ≤ 10 had better probability of response compared with pts with BCR-ABL% (IS) > 10 (62% vs 35%, respectively). This difference in MCyR rate was most significant for pts with baseline mutations (60% vs 19%, P = .006) and those with imatinib resistance (63% vs 33%, P = 0.0007). A similar trend was observed for patients without baseline mutations (64% vs 47%) and imatinib intolerance (57% vs 40%). BCR-ABL% (IS) at 3 mos was highly predictive of MMR rates at 24 mos (Table). Pts with BCR-ABL% (IS) values > 0.1 - ≤ 1 had significantly higher probability (65%) of achieving MMR for all patient groups, whereas those with BCR-ABL% (IS) > 10 had estimated rates of 10% or less. The BCR-ABL% (IS) value at 3 mos was also found to correlate with EFS at 24 mos (Table). The estimated EFS rate at 24 mos was highest for pts with BCR-ABL% (IS) values of ≤ 1 at 3 mos for each patient group and ranged from 75% to 100%. Patients with BCR-ABL% (IS) values > 10 at 3 mos had the poorest outcome and the estimated EFS rates ranged from 36% for patients with baseline mutations to 57% for those without baseline mutations. Conclusion: BCR-ABL% (IS) at 3 mos predicts response and long-term outcomes of imatinib-resistant and intolerant pts regardless of baseline mutation status at 24 mos on nilotinib therapy. Rapid reduction of BCR-ABL may be important for optimal response and outcome. Pts whose BCR-ABL % (IS) levels decreased below 10% at 3 mos demonstrated a high probability of achieving MMR and MCyR at 24 mos. Pts who achieve early molecular response may also have an increased probability of improved long-term outcomes on nilotinib therapy, while pts with BCR-ABL% (IS) value > 10 at 3 mos may have poorer prognosis. Disclosures: Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Haque:Novartis: Employment. Shou:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding.

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Update On Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) On Nilotinib Therapy at 24 Months: Clinical Response, Safety, and Long-Term Outcomes.

Blood ◽

10.1182/blood.v114.22.1129.1129 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1129-1129 ◽

Cited By ~ 15

Author(s):

Hagop M. Kantarjian ◽

Francis J. Giles ◽

Kapil N. Bhalla ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cytogenetic Response ◽

Study Entry ◽

Advisory Committees ◽

Transcript Levels ◽

Imatinib Resistant ◽

Efficacy Parameters

Abstract Abstract 1129 Poster Board I-151 Background Nilotinib is a selective and potent BCR-ABL inhibitor, developed through structure-based drug design, indicated for the treatment of Philadelphia chromosome positive (Ph+) CML patients in CP or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. Recently, 24-month follow-up data from the pivotal nilotinib 2101 study demonstrated achievement of rapid and durable cytogenetic responses in the majority of patients and an excellent overall survival (OS) rate of 87%. The current update focuses on the major molecular response (BCR-ABL transcript levels ≤ 0.1% according to the international scale; MMR) of patients treated with nilotinib. Methods Imatinib-resistant and -intolerant CML-CP patients (n=321) were treated with nilotinib 400 mg twice daily and followed for at least 24 months. In this report, the efficacy parameters studied were: rate of MMR, rate of major and complete cytogenetic response (MCyR, CCyR), time to and duration of response, time to progression (TTP), and OS. Efficacy parameters were also analyzed based on the presence or absence of a CHR at study entry. Results The median duration of exposure to nilotinib was 18.7 months (< 1.0–36.5), with 62% of patients on therapy for at least 12 months and 42% on therapy for ≥ 24 months. Median dose intensity of nilotinib was 788.5 mg/day, very close to planned dosing. Overall, 58% of patients required dose interruption (defined conservatively ≥ 1 day of interruption regardless of reason) with a median cumulative duration of interruption of 20 days (4% of days of exposure). Importantly, 73% of patients that required treatment interruptions resumed treatment after interruption at the planned dose. The achievement of MMR in imatinib-resistant and -intolerant CML-CP patients who had BCR-ABL transcript levels available post-baseline (n=294) were included in this efficacy analysis (Table). Of these patients, 105/294 (36%) entered the study with a CHR and 189/294 (64%) did not have a CHR at study entry. The overall MMR rate was 28%; MMR was higher in patients with CHR at study entry (38% vs. 22%). Overall, CCyR was achieved in 46% of patients, among whom 56% achieved MMR. Median time to MMR was 5.6 months. Overall, 77% and 84% of responding patients maintained MCyR and CCyR at 24 months, respectively. Overall (n=321), the estimated rate of progression-free survival (PFS), defined as progression to AP/BC or discontinuation due to progression or death, at 24 months was 64%, however, only 9 patients (3%) progressed to AP/BC based on actual laboratory values. PFS rate at 24 months was higher for patients with baseline CHR (77%) compared with patients without CHR at study entry (56%). OS at 24 months is 87% for the entire patient population. The safety profile of nilotinib remains unchanged at 24 months of follow-up. The majority of first episodes of grade 3/4 bilirubin and lipase elevations occurred within the first month of therapy and were brief in duration (median duration 15 days). The incidences of hepatic and pancreatic disorders on nilotinib were 1.3 and 1.7 per 100-patient years of therapy and no cumulative risk of hepatic and pancreatic events was observed in this population with longer follow-up. Importantly, discontinuations due to hepatobiliary adverse events were uncommon (n=2; < 1.0%). Conclusions Nilotinib therapy led to the achievement of MMR in a majority of patients with CCyR, and in 38% of patients with CHR at study entry. Furthermore, the response and outcomes of patients treated with nilotinib was higher in patients with CHR at baseline suggesting that patients with imatinib resistance and intolerance who lost cytogenetic response but not hematologic response have a more favorable response compared to those patients who have lost hematologic response when switched to nilotinib. Overall, the safety profile of nilotinib remains well-tolerated with long-term follow-up. At 24 months, nilotinib therapy remains an effective and tolerable therapy for patients with imatinib-resistant or -intolerant CML. Disclosures Kantarjian: Novartis: Research Funding. Giles:Novartis: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; Clavis: Research Funding. Bhalla:Novartis: Honoraria, Research Funding; Merck: Honoraria. Pinilla-Ibarz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis, Celgene: Honoraria, Participation in Advisory Boards on deferasirox clinical trials, Research Funding. Ottmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Radich:Novartis: Consultancy, Honoraria, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Martinelli:Novartis: Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Shou:Novartis: Employment. Gallagher:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. le Coutre:Novartis: Honoraria, Research Funding; BMS: Honoraria.

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Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽

10.1182/blood.v114.22.1130.1130 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1130-1130 ◽

Cited By ~ 1

Author(s):

Jerald P. Radich ◽

Giovanni Martinelli ◽

Andreas Hochhaus ◽

Enrico Gottardi ◽

Simona Soverini ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Advisory Committees ◽

Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

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ENESTnd Update: Nilotinib (NIL) Vs Imatinib (IM) In Patients (pts) With Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) and The Impact Of Early Molecular Response (EMR) and Sokal Risk At Diagnosis On Long-Term Outcomes

Blood ◽

10.1182/blood.v122.21.92.92 ◽

2013 ◽

Vol 122 (21) ◽

pp. 92-92 ◽

Cited By ~ 27

Author(s):

Giuseppe Saglio ◽

Andreas Hochhaus ◽

Timothy P. Hughes ◽

Richard E. Clark ◽

Hirohisa Nakamae ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Eligibility Criterion ◽

Molecular Response ◽

Newly Diagnosed ◽

Long Term Outcomes ◽

Vascular Events ◽

Advisory Committees ◽

The Impact

Abstract Introduction Frontline NIL continues to show benefit over IM in pts with Philadelphia chromosome-positive (Ph+) CML-CP, with higher rates of major molecular response (MMR; BCR-ABLIS ≤ 0.1%) and MR4.5 (BCR-ABLIS ≤ 0.0032%), lower rates of progression to accelerated phase (AP)/blast crisis (BC) and fewer new BCR-ABL mutations on treatment in the Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Pts (ENESTnd) trial. Here, we report data with a minimum follow-up (f/u) of 4 y; updated data based on 5 y of f/u will be presented. Methods Adults with newly diagnosed Ph+ CML-CP (N = 846) were randomized to NIL 300 mg twice daily (BID; n = 282), NIL 400 mg BID (n = 281), or IM 400 mg once daily (QD; n = 283). Progression and overall survival (OS) events were collected prospectively during study f/u, including after discontinuation of study treatment. Efficacy in the NIL 300 mg BID and IM arms was evaluated based on achievement of EMR (BCR-ABLIS ≤ 10% at 3 mo). Results At 4 y, ≥ 87% of pts remained on study in each arm and 57%-69% remained on core treatment (Table). Rates of MMR and MR4.5 by 4 y were significantly higher with NIL vs IM. Significantly fewer pts progressed to AP/BC on NIL vs IM (on core treatment: 0.7%, 1.1%, and 4.2%; on study: 3.2%, 2.1%, and 6.7% [NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively]). Of 17 pts across the 3 arms who progressed on core treatment, 11 (65%) had never achieved complete cytogenetic response and none had achieved MR4.5. Fewer mutations have emerged in the NIL arms vs the IM arm; in y 4, mutations emerged in 2 pts (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM). More pts achieved EMR in the NIL 300 mg BID arm vs the IM arm (91% vs 67%). Pts with EMR had significantly higher rates of progression-free survival (PFS) and OS at 4 y vs pts with BCR-ABL > 10% at 3 mo. Among pts with BCR-ABL > 10% at 3 mo, more progressions to AP/BC occurred in the IM arm (n = 14) vs the NIL 300 mg BID arm (n = 2); half of these pts progressed between 3 and 6 mo. In pts with intermediate or high Sokal risk, PFS and OS at 4 y were higher in both NIL arms vs the IM arm. No new safety signals were detected. Selected cardiac and vascular events were more common on NIL vs IM (by 4 y, peripheral arterial occlusive disease [PAOD] in 4 [1.4%], 5 [1.8%], and 0 pts; ischemic heart disease [IHD] in 11 [3.9%], 14 [5.1%,] and 3 [1.1%] pts; and ischemic cerebrovascular events in 3 [1.1%], 5 [1.8%], and 1 [0.4%] pts in the NIL 300 mg BID, NIL 400 mg BID, and IM arms, respectively). In the NIL 300 mg BID arm, 2 of 11 IHD events occurred between 3 and 4 y (all 4 PAOD events occurred in the first 2 y). In the NIL 400 mg BID arm, 2 of 5 PAOD events and 3 of 14 IHD events occurred between 3 and 4 y. Most pts (7 of 9) with a PAOD event on NIL were at high risk due to a combination of baseline risk factors. Conclusions NIL, a standard-of-care frontline therapy option for newly diagnosed CML-CP pts, affords superior efficacy compared with IM, including higher rates of EMR (which is associated with improved long-term outcomes), higher rates of MR4.5 (a key eligibility criterion for many studies of treatment-free remission), and a lower risk of disease progression. NIL continues to show good tolerability with long-term f/u. While selected cardiac and vascular events (including PAOD) are slightly more frequent on NIL vs IM, no increase in annual incidence of these events over time has been observed. Disclosures: Saglio: ARIAD: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Hochhaus:Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding. Hughes:Ariad: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CSL: Research Funding. Clark:Pfizer: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau. Nakamae:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau, travel/ accomodations/ meeting expenses Other. Kim:BMS, Novartis,IL-Yang: Honoraria; Pfizer: Consultancy, Research Funding. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Flinn:Novartis: Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Moiraghi:Bristol Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau. Fan:Novartis: Employment. Menssen:Novartis: Employment. Kantarjian:Novartis: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; ARIAD: Research Funding. Larson:Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy.

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Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Blood ◽

10.1182/blood-2019-122230 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1650-1650 ◽

Cited By ~ 3

Author(s):

B. Douglas Smith ◽

Tim H Brümmendorf ◽

Gail J. Roboz ◽

Carlo Gambacorti-Passerini ◽

Aude Charbonnier ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Employment Equity ◽

Advisory Committees ◽

Imatinib Resistant ◽

Equity Ownership

Introduction: The tyrosine kinase inhibitor (TKI) bosutinib is approved for patients with Philadelphia chromosome (Ph)+ chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed patients in chronic phase (CP). Methods: The ongoing phase 4 BYOND study (NCT02228382) is further evaluating the efficacy and safety of bosutinib for CML resistant/intolerant to prior TKIs. Patients were administered bosutinib at a starting dose of 500 mg once daily (QD). Primary results were previously reported. Here, we report the efficacy of bosutinib 500 mg QD in patients with Ph+ CP CML and resistance to imatinib (but not to nilotinib or dasatinib) vs patients with resistance to ≥1 second-generation TKI (dasatinib and/or nilotinib), as well as in patients with intolerance to all prior TKIs. Data are reported at ≥1 year after last enrolled patient; 85% of patients had a minimum follow-up of 2 years. Results: Of 163 patients who received bosutinib, 156 had Ph+ CP CML: 52 had resistance only to imatinib, 31 had resistance to dasatinib/nilotinib, and 73 were intolerant to all prior TKIs. Corresponding median treatment duration (range) was 24.1 (0.2-42.2), 8.9 (0.9-41.6), and 25.3 (0.4-41.9) months, and median dose intensity (range) was 360 (125-500), 431 (195-561) and 292 (80-500) mg/day. In all, 69.2%, 41.9%, and 53.4% of imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, were still receiving treatment as of the data cutoff date. The main reason for discontinuation was adverse events (AEs), with 10 (19.2%), 8 (25.8%), and 21 (28.8%) imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, discontinuing due to AEs. Corresponding discontinuations due to insufficient response occurred in 2 (3.8%), 5 (16.1%), and 1 (1.4%) patients. No patient experienced on-treatment transformation to advanced phase CML or discontinued treatment due to disease progression. In the evaluable cytogenetic population, cumulative major cytogenetic response (MCyR) rates were 85.4%, 69.0%, and 88.1% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively (Table). The majority of patients, across all cohorts, achieved a complete cytogenetic response (CCyR). In the evaluable molecular population, cumulative major molecular response (MMR) rates were 72.3%, 44.8%, and 82.2% in imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively; the 50th percentile of the cumulative incidence curve was 5.66 months, not reached and 3.22 months, respectively. Correspondingly, 59.6%, 24.1%, and 68.5% achieved molecular response (MR)4, and 48.9%, 17.2%, and 56.2% achieved MR4.5. In imatinib-resistant, dasatinib/nilotinib-resistant, and TKI-intolerant patients, respectively, Kaplan-Meier estimated overall survival rates (95% confidence interval) were 96.1% (85.2-99.0), 100% (100-100), and 98.6% (90.5-99.8) at 1 year, and 96.1% (85.2-99.0), 92.6% (73.4-98.1), and 97.2% (89.2-99.3) at 2 years with 4, 3, and 3 deaths occurring on study. Conclusions: Cytogenetic and molecular responses were seen in a high proportion of patients with Ph+ CP CML and TKI-resistance or TKI-intolerance. Response rates were similar between patients with resistance to imatinib and patients who were intolerant to all prior TKIs. Although to a lesser degree, responses were also seen in patients with resistance to second-generation TKIs, including patients achieving MR despite the shorter treatment duration. These results further support bosutinib use for patients with Ph+ CP CML and resistance/intolerance to prior TKIs. Disclosures Smith: Agios: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jazz: Consultancy. Brümmendorf:Janssen: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Merck: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding. Roboz:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding. Charbonnier:Novartis: Consultancy; Pfizer: Consultancy; Incyte: Speakers Bureau. Viquiera:Pfizer: Employment, Equity Ownership. Leip:Pfizer: Employment, Equity Ownership. Giles:Novartis: Consultancy; Epigene Therapeutics Inc: Consultancy, Other: leadership, stock/other ownership ; Actuate Therapeutics Inc: Employment. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; MSD: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽

10.1182/blood-2019-122152 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1828-1828

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

Erik Eckhert ◽

Stanley Schrier ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Response ◽

Al Amyloidosis ◽

Long Term Outcomes ◽

Advisory Committees ◽

Renal Response ◽

Cardiac Responses ◽

Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

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Maintaining Imatinib ≥600 Mg Daily in the First 12 Months of Chronic Phase CML Treatment Is Associated with Superior Event-Free Survival at 5 Years.

Blood ◽

10.1182/blood.v114.22.1125.1125 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1125-1125 ◽

Cited By ~ 1

Author(s):

Michael P Osborn ◽

Susan Branford ◽

Deborah L White ◽

John F Seymour ◽

Ruth Columbus ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Event Rates

Abstract Abstract 1125 Poster Board I-147 The Australasian Leukaemia and Lymphoma Group conducted a trial (TIDEL I) in 103 patients with newly diagnosed chronic phase CML, using imatinib 600 mg/day with dose escalation to 800 mg/day for suboptimal response. This was defined as failure to achieve (1) complete haematological response (CHR) at 3 months, (2) major cytogenetic response (MCR) at 6 months, (3) complete cytogenetic response (CCR) or molecular equivalent at 9 months, or (4) less than 0.01% (IS) BCR-ABL by RQ-PCR at 12 months. Here we report the outcomes with all surviving patients having been treated for at least 60 months. We aimed to determine whether the patient outcome at 60 months was predicted by the molecular response within the first 18 months of imatinib therapy. The outcomes for patients maintaining a dose of imatinib of ≥600 mg/day in the first 12 months was compared to those who were on a reduced dose for at least part of this time. Event-free survival (EFS) was defined as death from any cause, accelerated phase/blast crisis (AP/BC), and loss of CHR, MCR or CCR. The 103 patients included 66 males and 37 females with a median (±SD) age of 49 (±14) years. All patients had an ECOG performance status of 0-2 at enrolment. The 5-year EFS was 71%, transformation (AP/BC) free survival (TFS) was 95%, and overall survival was 87%. Of the 14 patients who died, 3 died in blast crisis, 2 from transplant-related complications, 8 from CML-unrelated causes, and the cause of death of 1 patient was unavailable. The annual rates of progression to AP/BC over 5 years were 3%, 1%, 0%, 1%, and 0%, while annual event rates were 13%, 8%, 8%, 1%, and 4%. CCR was achieved by 89% of patients by 60 months, while 72% achieved a major molecular response (MMR) by this time. In the first 12 months of treatment, 55% of patients maintained an imatinib dose of ≥600 mg/day (mean ±SD dose = 604 ±10 mg/day), while 45% were on <600 mg/day for at least part of this time (mean ±SD dose = 511 ±100 mg/day). EFS at 60 months was significantly higher in patients taking ≥600 mg/day compared with those who had been dose-reduced to <600 mg/day (89% vs 56%, P<0.001). Annual event rates for the ≥600 mg/day group were 6%, 2%, 2%, 0%, and 2%, while annual event rates for those on <600 mg/day were 14%, 16%, 16%, 8%, and 4%. By 60 months, 96% of patients who had been on ≥600 mg/day within the first 12 months had achieved CCR, while only 80% of those who had been on <600 mg/day had achieved this milestone (P<0.001). Log rank analysis of the achievement of MMR was also significant (P=0.03). Overall survival and TFS after 12 months were both similar between the dosing groups. There was no difference between the dosing groups' median age (50 vs 48 years, P=0.36) or Sokal score (1.04 vs 0.94, P=0.33) that may otherwise account for these results. The outcome was also determined for all patients dependent on the BCR-ABL levels at various assessment timepoints. Patients with a BCR-ABL level of <10% (IS) at 6 months (n=92) had an EFS of 78% at 60 months, while all of those with a level >10% (IS) (n=8) had an event (P<0.001). Patients with a level of ≤1% (IS) at 12 months (equivalent to CCR) (n=81) had an EFS of 75% compared with 25% (n=13) for those with levels >1% (IS) (P<0.001). At 18 months, a level ≤0.1% (IS) (n=58) conferred an EFS of 88%, while those who had failed to attain this depth of response (n=30) had an EFS of 60%. There was a significant difference in EFS between those who had achieved an MMR at 18 months and those who had achieved a CCR, but no MMR (88% vs 67%, P=0.03). In conclusion, our data suggest that patients maintaining a dose of ≥600mg in the first 12 months of imatinib therapy are more likely to achieve CCR and MMR, and superior EFS compared to those with a lower dose. This study also confirms that achieving an MMR by 18 months is associated with improved EFS. This emphasises the value of achieving a molecular response early in the treatment course, as well as adding weight to the evidence supporting the role of molecular monitoring in CML. Disclosures Branford: Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. White:Novartis and Britol-Myers Squibb: Research Funding. Seymour:Bayer Schering: Consultancy, Membership on an entity's Board of Directors or advisory committees, Travel grants; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel Grants. Catalano:Roche: Honoraria, Research Funding, Travel grants. Mills:Celgene Pty Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding.

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Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽

10.1182/blood.v114.22.3286.3286 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3286-3286 ◽

Cited By ~ 5

Author(s):

Philipp D. le Coutre ◽

Anna Turkina ◽

Dong-Wook Kim ◽

Bernadeta Ceglarek ◽

Giuliana Alimena ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Study Drug ◽

Cytogenetic Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Imatinib Resistant ◽

Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

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Outcome of Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) with Relapse After Tyrosine Kinase Inhibitor (TKI) Therapy

Blood ◽

10.1182/blood.v118.21.1518.1518 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1518-1518

Author(s):

Hun Ju Lee ◽

Susan O'Brien ◽

Hagop M. Kantarjian ◽

Farhad Ravandi ◽

Stefan Faderl ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Cytogenetic Response ◽

Molecular Response ◽

Major Molecular Response ◽

Advisory Committees ◽

Cns Relapse ◽

Complete Hematologic Response

Abstract Abstract 1518 Background: Treatment with TKIs has greatly improved the outcome of patients with Ph+ ALL. However, many patients treated with TKI-based therapy eventually have a relapse. The response to salvage therapy and long-term outcomes of these patients are unknown. Aims: Describe the outcomes of patients with Ph+ ALL with resistance to or relapse after frontline TKI-based chemotherapy. Methods: We analyzed the outcome of patients who were treated in clinical trials at our institution between February 2001 and July 2008 with TKI-based chemotherapy for newly diagnosed Ph+ ALL who had refractory or relapsed disease. Results: One hundred thirteen patients were treated with frontline hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (HCVAD) plus imatinib (HCVAD+I; n=54) or HCVAD plus dasatinib (HCVAD+D; n=59). Of these, 35 (31%) experienced primary resistance (n=1) or relapse (n=34). The median age was 51 years [range (r): 20–85]; 12 patients (34%) were older than 60 years. Median follow-up was 21.1 mo (r: 4.2–56.7). Median white blood cell and platelet counts at diagnosis were 14.4 × 109/L (r: 1.2–292.9) and 48 × 109/L (r: 4–425), respectively. White blood cell count was >30 × 109/L in 13 patients (37%). Median peripheral and bone marrow blast percentages were 53% (r: 0–97%) and 80% (r: 1–98%), respectively. Twenty-two patients (63%) had received HCVAD+I and 13 (37%) HCVAD+D. Twenty-three patients (66%) had experienced first complete remission (CR1) with 1 cycle of induction. Median CR1 duration was 12 mo (r: 1.9–42). Four patients underwent allogeneic stem cell transplantation (ASCT) in CR1. ABL kinase domain mutations were investigated in 28 patients (80%) at relapse; 16 (57%) had mutations, including 5 (14%) with T315I (all had received HCVAD+D). Upon relapse, 31 patients received first salvage therapy (S1), 24 with chemotherapy [HCVAD+D, n=8; HCVAD+I, n=3; HCVAD+nilotinib (N), n=1; HCVAD+asparaginase (Asp), n=1; methotrexate, vincristine, Asp, and dexamethasone (MOAD), n=2; others, n=9]; 6 with a TKI only (I, n=2; D, n=1; N, n=1; others, n=2); and 1 with ASCT. Three patients were unfit for treatment. Median cycles of S1 were 2 (r: 1–8). Thirteen patients (42%) had second complete remission (CR2) (HCVAD+D, n=6; HCVAD+I, n=2; HCVAD+N, n=1; HCVAD+Asp, n=1; others, n=3). Median time to CR2 was 1.5 mo (r: 0.7–8.8). Five patients underwent ASCT in CR2. Median CR2 duration was 7.3 mo (r: 1.4–36.2). Complete cytogenetic response was seen in 11 patients (35%); major molecular response (BCR-ABL/ABL ratio <0.05%) in 9 (29%); and complete molecular response in 7 (22%); and complete hematologic response in 15 (48%). Times to complete cytogenetic response and complete molecular response were 1.3 mo (r: 0.7–10.6) and 3 mo (r: 1.5–8.7), respectively. Seven patients had second relapse. Fifteen patients (7 relapse, 8 refractory) received second salvage therapy (S2) with systemic chemotherapy (MOAD, n=2; phase I/single-agent TKI, n=8; others, n=5); 1 patient had solitary central nervous system (CNS) relapse treated with intrathecal cytarabine and methotrexate. CR3 was obtained in 1 patient, the patient with sole CNS relapse. Median disease-free survival (DFS) and overall survival (OS) after S1 were 6.5 mo (r: 0.5–45) and 7.3 mo (r: 1.4–36.2), respectively. At last follow-up, 2 patients (6%) were alive and 33 had died, 11 (33%) of infectious complications, 5 (15%) of organ failure, 3 (9%) of bleeding complications, 2 (6%) of graft-versus-host disease complications, 2 (6%) of CNS relapse, and 10 (30%) of other or unknown causes. Median OS after S2 was 2.1 mo (r: 1.4–2.6). In univariate analysis, age >60 years was associated with worse OS after S1 [4.2 vs. 12.7 mo; 95% confidence interval (CI) 1.8 to 6.7 vs. 7.5 to 17.9 (P=0.006)]. Complete hematologic response was associated with improved OS after S1 [15.4 vs. 4.3 mo; 95% CI 9.1 to 21.8 vs. 2.5 to 6.0 (P<0.001)]. Major molecular response was associated with improved OS after S1 [18.1 vs. 5.7 mo; 95% CI 9.3 to 26.8 vs. 3.6 to 7.8 (P=0.003)]. Choice of prior TKI (HCVAD+I vs. HCVAD+D) did not significantly influence CR and OS after relapse. Conclusion: Patients with refractory or relapsed Ph+ ALL after TKI-based therapy have poor outcome, particularly those who are older or have persistent BCR/ABL transcripts. New agents are needed to improve the outcome in this population. Disclosures: Kantarjian: BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Nilotinib in Imatinib-Resistant or -Intolerant Patients (pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): 48-Month Follow-up Results of a Phase 2 Study,

Blood ◽

10.1182/blood.v118.21.3770.3770 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3770-3770 ◽

Cited By ~ 3

Author(s):

Philipp D. le Coutre ◽

Francis J. Giles ◽

Javier Pinilla-Ibarz ◽

Richard A. Larson ◽

Norbert Gattermann ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Lung Neoplasm ◽

Chronic Phase ◽

Dose Intensity ◽

Advisory Committees ◽

Imatinib Resistance ◽

Imatinib Resistant ◽

Significant Difference

Abstract Abstract 3770 Background: Nilotinib is a selective and potent BCR-ABL TKI approved for the treatment of pts with newly diagnosed Ph+ CML-CP, and for pts with CML-CP or CML-AP resistant to or intolerant of imatinib. Here, we present the 48-mo follow-up data from the 2101 trial for pts with imatinib resistance or intolerance. Methods: Pts were treated with nilotinib 400 mg twice daily (BID). Key endpoints included PFS (defined as progression to AP/BC or discontinuation due to disease progression as assessed by investigator or death from any cause) and OS (includes deaths during treatment or follow-up after discontinuation). Results: 321 pts were enrolled (70% imatinib resistant; 30% imatinib intolerant with resistance). At baseline (BL), 36% of pts were in CHR. At the time of data cutoff, 224/321 pts (70%) discontinued nilotinib therapy (Table), and 31% of all pts had at least 48 mo of treatment. The median nilotinib dose intensity was 789 mg/day (range, 151–1110) and 62% of pts received ≥ 400 mg BID nilotinib as their last dose available. Pts with BL CHR had a significantly higher PFS rate at 48 mo vs pts without BL CHR (71% vs 49%, respectively; P =.001). Only 11 (3%) pts progressed to advanced disease (AP/BC) during study. Estimated 48-mo OS rate was 78% (95% CI 74%-83%). Among resistant pts, those without BL mutations (n = 92) had a significantly higher OS rate at 48 mo vs pts with sensitive mutations at BL (n = 78) (84% vs 74%, respectively, P =.029); however, there was no significant difference in OS among pts with sensitive and insensitive mutations (Y253H, E255K/V or F359C/V, n = 27) at BL (74% vs 71%, respectively, P =.804). No new safety signals were observed, and few additional AEs were reported since 24 mo follow-up (Table). Biochemical lab abnormalities were generally mild, transient, and easily managed; grade 3/4 lipase elevation (19%), hypophosphatemia (18%), and hyperglycemia (13%) were most common. Reports of any-grade pleural effusions remained low (1%), and no new cases were reported with longer follow-up. No new cases of QTcF >500 ms and 3 new cases of QTcF increases > 60 ms from BL were reported. Nine pts died during treatment or within 28 days of discontinuation: 8 deaths were previously reported and occurred in the first 24 mo of follow-up; 1 additional death due to lung neoplasm occurred between 24 and 48 mo (35 mo). Conclusions: With longer follow up, nilotinib continues to be effective and well tolerated in pts with Ph+ CML-CP resistant to or intolerant of imatinib therapy. Nilotinib prevented progression to AP/BC in the majority of pts on treatment and was associated with high OS rates. No cumulative toxicity was observed. Data demonstrating the higher rate of PFS in pts who entered the study with a BL CHR suggest that switching pts to nilotinib prior to hematologic failure on imatinib, and according to current treatment guidelines, may maximize the efficacy of nilotinib therapy. Disclosures: le Coutre: Novartis: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria. Giles:Novartis: Consultancy, Honoraria, Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau. Larson:Novartis: Consultancy, Honoraria, Research Funding. Gattermann:Novartis: Honoraria, Research Funding. Ottmann:Novartis: Consultancy; BMS: Consultancy, Research Funding. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Radich:BMS: Consultancy; Novartis: Consultancy, Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Branford:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Research Funding; Ariad: Research Funding. Müller:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Shou:Novartis: Employment. Novick:Novartis: Employment, Equity Ownership. Fan:Novartis: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Baccarani:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding.

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Impact of Early Progression on Long Term Outcomes Among Myeloma Patients Receiving Lenalidomide, Bortezomib, and Dexamethasone (RVD) Induction Therapy

Blood ◽

10.1182/blood-2018-99-120314 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3302-3302

Author(s):

Ajay K Nooka ◽

Jonathan L Kaufman ◽

Charise Gleason ◽

Nisha Joseph ◽

Craig C Hofmeister ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Long Term Outcomes ◽

Advisory Committees ◽

Term Survival ◽

Risk Status ◽

Early Progression

Abstract Background: The incorporation of modern day induction regimens, autotransplant and continuous maintenance has resulted in better long-term outcomes for myeloma patients. Experience and trials demonstrated that by prolonging 1st progression-free survival (PFS1) and pushing the relapse farther, we can gain the OS advantage (McCarthy et al NEJM 2012). Unfortunately, a subgroup of patients fail to exploit this advantage, either due to their disease biology or due to inadequate therapy and suffer early progression (inferior PFS1) that impacts their long term outcomes. First, we evaluated the predictors of early progression to highlight the modifiable factors that can prevent progression. Next, we quantified the impact of shorter PFS1 (<36 months) on the long-term survival (OS). Methods: Of the 1000 consecutive newly diagnosed myeloma patients treated with homogenous induction therapy (RVD) induction therapy per Richardson et al (Blood 2010) from July 2005 until August 2016, 230 patients progressed within the first 36 months while 96 patients progressed beyond the 36-month mark, at the time of analysis. Median follow up duration was 38 months. Demographic and outcomes data for the pts were collected from myeloma database and responses were evaluated per IMWG Uniform Response Criteria. Results: Median age of the pts is 60 years (range 29-78). 29% of the patients are above the age of 66. M/F 54%/46%; W/AA 60%/32%; ISS III 27% were other patient characteristics. Cytogenetic abnormalities of significance: t(11;14): 13.5%, t(4;14): 7.8%, t(14;16): 5% del 17p: 16%, complex cytogenetics: 29% and high-risk status was conferred to 44% of the patients. 83% of patients underwent an autotransplant and median time to transplant was 6 (2-50) months. 68% of patients received maintenance therapy. Response rates are summarized in Fig 1. The median PFS for early and non-early progressors were 32 months (95% confidence interval (CI), 30.293-33.707) and 101 months (95% CI, 77.14-124.86) months, respectively (P<0.001). The median overall survival (OS) for early progressors was 94 months, and non-early progressors was not reached. (Fig 2). Among the predictors of early relapse, presence of high-risk status, ISS stage 3, inability to achieve ≥VGPR after transplant, non-receipt of transplant and/or maintenance were independent predictors of early progression on the multivariate analysis as illustrated in Table 1. Conclusions: Even with the effective use of the 3-drug induction regimen, these functionally high-risk patients that are early progressors have truncated long term survival. Our analysis advocates for using transplant, deepening the responses with modern drugs such as monoclonal antibodies to achieve ≥VGPR after transplant and intense maintenance strategies to prevent relapse. Disclosures Nooka: Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kaufman:Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Roche: Consultancy; Janssen: Consultancy; BMS: Consultancy. Hofmeister:Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Boise:AstraZeneca: Honoraria; Abbvie: Consultancy. Heffner:ADC Therapeutics: Research Funding; Kite Pharma: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding. Lonial:Amgen: Research Funding.

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